Tumour concentrations of flavone acetic acid (FAA) in human melanoma: comparison with mouse data

Abstract

Flavone acetic acid (FAA) showed impressive effects against murine solid tumours but no activity in clinical studies. The mechanism of action in mice may involve damage to tumour vasculature or immunomodulation, and these effects may be species-specific. Alternatively, concentrations of FAA achieved in mouse tumours may be higher than in human tumours. It is important to resolve this issue since it raises important questions about the relevance of in vitro versus in vivo tumour screens and the development of FAA analogues. As part of a Cancer Research Campaign Phase II study of metastatic melanoma in which 8.4 g m-2 FAA was given as a 6 h infusion, six tumour biopsies were obtained from four patients. FAA tumour concentrations were determined by HPLC and compared with subcutaneous murine solid tumours within the same analytical laboratory. Tumour/plasma percentages (range 26-61%; mean +/- SD, 43.9 +/- 11.4%) were similar to those in mice, as was the area under the curve (AUC) extrapolated to infinity and the AUC above the putative activity threshold of 100 micrograms ml-1. We conclude that the exposure of drug-refractory human melanoma tissue to FAA was comparable to that of sensitive mouse tumours. This suggests that reduced penetration of FAA into human tumours is unlikely to explain the lack of antitumour activity observed in clinical studies and that differences in mechanism of action are predominant.